An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype.
An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype.
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DOI：
10.1186/gm444
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发表时间：
2013
期刊：
影响因子：
12.3
通讯作者：
Firestein GS
中科院分区：
文献类型：
--
作者：
Whitaker JW;Shoemaker R;Boyle DL;Hillman J;Anderson D;Wang W;Firestein GS
DNA甲基化特征已被表征为区分类风湿性关节炎（RA）成纤维细胞样滑膜细胞（FLS）与骨关节炎（OA）FLS。在长期培养的细胞中存在表观遗传变化表明类风湿FLS印迹可能有助于致病行为。为了了解差异甲基化基因（DMG）如何参与RA的发病机制，我们评估了RA特征的稳定性以及DMG是否在特定的通路和本体论类别中富集。为了评估RA甲基化特征，使用Illumina HumanMethylation 450芯片比较第3、5和7代RA、OA和正常（NL）FLS中的甲基化水平。然后在传代之间比较标记内CpG的甲基化频率。为了评估DMG在特定途径中的富集，将DMG鉴定为在其启动子区域内具有显著差异甲基化位点的基因。然后将这些DMG集与途径和本体数据库进行比较，以建立特定类别的富集。初始研究比较了RA、OA和NL的第3、5和7代FLS。无论传代数如何，每个单独的FLS系的差异甲基化模式都非常相似。使用最稳健的分析，与OA和NL FLS相比，RA的272条KEGG通路中有20条和34，400条GO通路中有43条发生了显著改变。最有趣的是，我们发现KEGG“风湿性关节炎”途径始终最显著地富集差异甲基化位点。其他途径涉及先天免疫（补体和凝血、Toll样受体、NOD样受体和胞质DNA传感）、细胞粘附（粘着斑、细胞粘附分子）和细胞因子（细胞因子-细胞因子受体）。总之，KEGG和GO途径分析表明RA FLS的非随机表观遗传印记。DNA甲基化模式包括与RA发病机制有关的关键基因的异常，并且对于多个细胞传代是稳定的。持续的表观遗传学改变可能有助于RA滑膜细胞的侵袭性表型，并确定可能调节致病行为的潜在治疗靶点。
A DNA methylation signature has been characterized that distinguishes rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) from osteoarthritis (OA) FLS. The presence of epigenetic changes in long-term cultured cells suggest that rheumatoid FLS imprinting might contribute to pathogenic behavior. To understand how differentially methylated genes (DMGs) might participate in the pathogenesis of RA, we evaluated the stability of the RA signature and whether DMGs are enriched in specific pathways and ontology categories. To assess the RA methylation signatures the Illumina HumanMethylation450 chip was used to compare methylation levels in RA, OA, and normal (NL) FLS at passage 3, 5, and 7. Then methylation frequencies at CpGs within the signature were compared between passages. To assess the enrichment of DMGs in specific pathways, DMGs were identified as genes that possess significantly differential methylated loci within their promoter regions. These sets of DMGs were then compared to pathway and ontology databases to establish enrichment in specific categories. Initial studies compared passage 3, 5, and 7 FLS from RA, OA, and NL. The patterns of differential methylation of each individual FLS line were very similar regardless of passage number. Using the most robust analysis, 20 out of 272 KEGG pathways and 43 out of 34,400 GO pathways were significantly altered for RA compared with OA and NL FLS. Most interestingly, we found that the KEGG 'Rheumatoid Arthritis' pathway was consistently the most significantly enriched with differentially methylated loci. Additional pathways involved with innate immunity (Complement and Coagulation, Toll-like Receptors, NOD-like Receptors, and Cytosolic DNA-sensing), cell adhesion (Focal Adhesion, Cell Adhesion Molecule), and cytokines (Cytokine-cytokine Receptor). Taken together, KEGG and GO pathway analysis demonstrates non-random epigenetic imprinting of RA FLS. The DNA methylation patterns include anomalies in key genes implicated in the pathogenesis of RA and are stable for multiple cell passages. Persistent epigenetic alterations could contribute to the aggressive phenotype of RA synoviocytes and identify potential therapeutic targets that could modulate the pathogenic behavior.
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影响因子：
14.9
作者：
Kanehisa M;Goto S;Sato Y;Furumichi M;Tanabe M
通讯作者：
Tanabe M
影响因子：
30.8
作者：
Landan, Gilad;Cohen, Netta Mendelson;Tanay, Amos
通讯作者：
Tanay, Amos
DOI：
10.1186/ar391
发表时间：
2002
期刊：
Arthritis research
影响因子：
--
作者：
Hirth A;Skapenko A;Kinne RW;Emmrich F;Schulze-Koops H;Sack U
通讯作者：
Sack U
影响因子：
6.8
作者：
Filkova, Maria;Juengel, Astrid;Gay, Steffen
通讯作者：
Gay, Steffen
影响因子：
56.9
作者：
Lee, David M.;Kiener, Hans P.;Brenner, Michael B.
通讯作者：
Brenner, Michael B.